Antimicrobial peptide, nisin, comoplexed with lipid II
Lactococcus lactis (lactic acid bacteria)
The discovery of penicillin, followed by the development of antibiotics, was one of the major achievements of pharmacology in the past century. Antibiotics helped doctors to defeat many deadly diseases. Antibiotics usually attack bacteria by disrupting the formation of their cell walls. This causes leakage of cytosolic content and consequently cell death. Unfortunately, over the years bacteria developed resistance towards these antibiotic agents by mutating the structure of their outer wall components. A new family of drugs, called lantibiotics, are expected to overcome this problem. Nisin, a member of this family, is a natural antimicrobial agent used as a preservative in heat processed and low pH foods. It is known to bind selectively to lipid II, the fundamental building block of the cell wall.
Here you can see the structure of the complex between nisin and lipid II. Nisin contains some unusual amino acids derived from dehydrated serine and threonine. By coupling to cysteine they produce the so-called lanthionine residues, therefore, the name - lanthionine-antibiotics. The nisin-lipid II binding motif is very unusual. The N-terminal part of nisin forms a cage-shaped structure which perfectly embraces the pyrophosphate part of lipid II by five hydrogen bonds. Then, after several conformational changes, it penetrates the membrane, stretching all the way to the cytoplasm. In this way pores are easily formed, and bacterial wall integrity is destroyed. Drug resistance in bacteria develops by mutations at drug binding sites but, because the pyrophosphate half of lipid II is fundamental for the construction of the bacterial wall, it can not be easily replaced by simple mutations. The nisin-lipid II system therefore can be used as an effective template for the design of novel anti-microbial medicaments.
Protein Data Bank (PDB)
Hsu, S.-T.D. Breukink, E. Tischenko, E. Lutters, M.A.G. De Kruijff, B. Kaptein, R. Bonvin, A.M.J.J. Van Nuland, N.A.J.; "The Nisin-Lipid II Complex Reveals a Pyrophosphate Cage that Provides a Blueprint for Novel Antibiotics"; Nat.Struct.Mol.Biol.; (2004) 11:963-967 PubMed:15361862.
author: Rossen Apostolov